Atopic dermatitis is an inflammatory skin disease responsive mainly to external stimuli, which is an “environmental-genetic” disorder where the reaction to an environmental stimulation is influenced by a genetic background. Further, it has been known that in many cases atopic dermatitis patients also develop other allergic diseases such as bronchial asthma.
Heretofore, it has commonly been considered that atopic dermatitis is caused by some kind of immune abnormality, and a plurality of immune-related genes have been reported as genes responsible for atopic dermatitis. Thus, all atopic dermatitis model animals reported so far have been induced to develop a similar symptom to atopic dermatitis by introducing or knocking-out a gene associated with the regulation of an immune function. Examples of such atopic dermatitis animal model include GATA-3 transgenic mouse (Patent Document 1), TNP-IgE transgenic mouse (Non-patent Document 1), IL-18 transgenic mouse (Non-patent Document 2), Caspase-1 transgenic mouse (Non-patent Document 3), Cathepsin E-knockout mouse (Non-patent Document 4), etc.
More recently, however, it has been suggested that skin-barrier functional disorder may be associated with the pathogenesis of atopic dermatitis. The skin-barrier function is to retain water in the body or to protect against a substance entering from outside, ultraviolet rays, etc. and the stratum corneum that is the outermost layer of the epidermis fulfils a particularly important function. The stratum corneum is constituted by cornified keratinocytes and consists of a keratin-filament skeletal construct surrounded by a special coat which is not found in other cells in the body. For the construction of this keratin-filament skeleton, filaggrin derived from epidermal keratinocytes is indispensable. Filaggrin is a protein produced specifically in epidermal keratinocytes, and immediately after the precursor, profilaggrin protein, is expressed, it is phosphorylated and accumulated in keratohyaline granules and then processed into filaggrin through a dephosphorylation and hydrolysis. Filaggrin acts to aggregate keratin-filaments, and in addition, is degraded further into low-molecular peptides that function as a moisturizing factor or ultraviolet absorption factor.
As a result of a number of studies on atopic dermatitis patients in Europe and the United States, a genetic mutation that could trigger atopic dermatitis was discovered on the gene encoding filaggrin protein (FLG gene). It has been revealed that this genetic mutation causes a complete loss of profilaggrin protein and filaggrin protein (Non-patent Document 5), and that this mutation is frequently found in atopic dermatitis patients, and more frequently in atopic dermatitis patients also having asthma (Non-patent Document 6). Further, it has been demonstrated also in Japan that a similar genetic mutation to FLG is frequently found in atopic dermatitis patients (Non-patent Document 7). These results imply that impaired skin-barrier function due to filaggrin protein deficiency is associated with the pathologies of atopic dermatitis and asthma. The present situation is, however, that the relation between such skin-barrier functional disorder and allergic diseases such as atopic dermatitis has attracted little attention heretofore, which has prevented the promotion of further study. It is believed that for the future establishment of a method for preventing and treating atopic dermatitis and/or asthma, an animal model in which skin-barrier function has been impaired due to profilaggrin and filaggrin deficiency is very useful.
As a method for producing a skin-disease animal model characterized by impaired skin-barrier function, a method of physically separating the stratum corneum by tape-stripping and a method of removing a lipid component constituting the skin-barrier function by an organic solvent such as acetone or by a surfactant are known (for example, Patent Document 2, Non-patent Document 10, and Non-patent Document 11). These animal models, however, do not reflect the skin-barrier functional disorder due to filaggrin deficiency, and thus are not suitable as a model animal for elucidating the pathogenesis of atopic dermatitis. Further, it has been revealed that a flaky tail (ft) mouse known as a ichthyosis vulgaris mouse model carries a recessive mutation in the vicinity of the gene region encoding loricrin and filaggrin that are proteins constituting the stratum corneum (Non-patent Document 8), and that, in the mouse epidermis, no normal profilaggrin protein (about 500 kDa) is produced, and a mutated profilaggrin protein of a smaller molecular weight (220 kDa) is expressed instead (Non-patent Document 8 and Non-patent Document 9). However, ft mice are considered to be inadequate for a model for atopic dermatitis patients who completely lacks profilaggrin protein and filaggrin protein, since (1) ft mice are spontaneously-generated mutant mice and therefore may carry a mutation in genes other than filaggrin gene, and (2) that even abnormal profilaggrin protein expressed in ft mice may be processed to generate filaggrin protein and filaggrin peptides. As stated above, no animal model has been established so far that has completely lost profilaggrin protein and filaggrin protein, which can be used as an atopic dermatitis model.